Despite the long-standing evidence of reduced bone density and increased fractures in patients with rheumatoid arthritis (RA), knowledge of the mechanisms underlying osteopenia is the disorder is lacking. While reduced mobility and glucocorticoid therapy may contribute to bone loss in RA, women with RA have reduced circulating estrogen and adrenal androgen levels (which are bone-sparing) and increased cytokines (which may stimulate bone resorption). The long range goal of this proposal is to elucidate the mechanisms underlying osteopenia in RA. Estrogen replacement therapy prevents bone loss in surgical and natural menopause, and may directly suppress cytokine-mediated osteoclast differentiation and bone resorption. The local production of cytokines and their suppression by estrogen will be directly assessed using a new cell culture technique developed for bone marrow harvested from discarded femurs in women with RA at the time of total joint replacement (TJR). We have used this new model to show 1.) the age-related increases in marrow osteoclastogenesis and generation of bone-resorbing cytokines and 2.) the suppression of marrow osteoclastogenesis and cytokine production in women receiving postmenopausal hormone-replacement therapy. We will critically test the hypothesis that reduced systemic sex steroids and elevated cytokines contribute to localized and generalized bone loss in RA.